Leona Ling1, Steven Tyler2, Christopher J. Beneduce3, Federico Zazzetti4, Faye Yu3, Julia Brown3, Sujatha Kumar5, Rui Xu6, Jay Duffner7 and William Avery8, 1Janssen Research & Development, LLC, Cambridge, MA, 2Genevant Therapeutics, Cambridge, MA, 3Janssen Research and Development, Cambridge, MA, 4Janssen Medical Affairs Global Services, LLC, Buenos Aires, Argentina, 5GlaxoSmithKline, Boston, MA, 6Janssen Research and Development, San Diego, CA, 7Faze Medicines, Cambridge, MA, 8Kisbee Therapeutics, Boston, MA
Background/Purpose: Nipocalimab, a fully human, effectorless IgG1 anti-neonatal Fc receptor (FcRn) monoclonal antibody, binds to FcRn with high affinity which prevents IgG recycling, leading to reduced serum levels of total IgGs, including pathogenic IgG autoantibodies. Rapid, sustained lowering of IgG was observed in the phase 2 VIVACITY study in generalized myasthenia gravis (gMG) and in phase 1 healthy volunteers. In gMG patients, nipocalimab induced rapid and sustained lowering of anti-AChR autoantibodies and MG-ADL scores, but no serious adverse events including clinically significant infections were observed. This study characterized the effect of nipocalimab on immune function.
Methods: Nipocalimab was evaluated extensively in vitro and in nonhuman primate-based chronic toxicology studies to evaluate selectivity, tolerability, safety and immunopharmacology. Safety, tolerability and immune-focused assessments in clinical phase 1 and phase 2 MG studies were also completed (NCT02828046, NCT03772587).
Results: Nipocalimab binds specifically in vitro to FcRn without activation of effector function or inhibition of antigen presentation. In nonhuman primates administered up to 300 mg/kg nipocalimab every week for up to 6 months, sustained lowering of IgG was observed without adverse effects. Immunotoxicology identified no effect on immune cell phenotypes; CD8 T cell, NK or innate cell functions; T-dependent neoantigen IgM responses. Neoantigen IgG production was observed, but with lowered peak IgG titers consistent with the anticipated increase in IgG clearance with nipocalimab. In clinical studies, nipocalimab demonstrated a reproducible selective decrease in total serum IgG, including all subclasses of IgG, with no effect on IgM, IgA, IgE, CH50, C3, C4, inflammatory cytokines or acute phase proteins including, C-reactive protein.
Conclusion: These data suggest that nipocalimab can selectively lower IgG and IgG autoantibodies while preserving cellular immunity, complete IgM response and IgG production after neoantigen challenge. Overall, nipocalimab's selective effect on IgG recycling provides a mechanistic rationale for potentially decreased infection risk despite substantial IgG lowering.
Disclosures: L. Ling, Janssen Research & Development, Johnson & Johnson; S. Tyler, Genevant Therapeutics; C. Beneduce, Janssen Research & Development, Johnson & Johnson; F. Zazzetti, Janssen Medical Affairs Global Services, LLC; F. Yu, Janssen Research & Development, Johnson & Johnson; J. Brown, Janssen Research & Development, Johnson & Johnson; S. Kumar, GlaxoSmithKline; R. Xu, Janssen Research & Development, Johnson & Johnson; J. Duffner, Faze Medicines; W. Avery, Kisbee Therapeutics.
